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Diabetes Volume 63, July 2014
Bilal Omar and Bo Ahrén
Pleiotropic Mechanisms for the
Glucose-Lowering Action of
DPP-4 Inhibitors
PERSPECTIVES IN DIABETES
Diabetes 2014;63:2196–2202 | DOI: 10.2337/db14-0052
Dipeptidyl peptidase (DPP)-4 inhibition is a glucoselowering treatment for type 2 diabetes. The classical
mechanism for DPP-4 inhibitors is that they inhibit DPP-4
activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide
(GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion,
in turn increasing glucose utilization and diminishing
hepatic glucose production, which, through reduction in
postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but
also to a limited degree in humans have found additional
mechanisms for DPP-4 inhibitors that may contribute to
their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which
prevents inactivation of newly released GLP-1, which in
turn augments GLP-1-induced activations of autonomic
nerves and results in high portal GLP-1 levels, resulting in
inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents
inactivation of locally produced intact GLP-1 in the islets,
thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation;
and 3) prevention of the inactivation of other bioactive
peptides apart from GLP-1, such as glucose-dependent
insulinotropic polypeptide, stromal-derived factor-1a, and
pituitary adenylate cyclase-activating polypeptide, which
may improve islet function. These pleiotropic effects may
contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.
Dipeptidyl peptidase (DPP)-4 inhibition is a strategy for
glucose-lowering treatment for type 2 diabetes (1). It was
Department of Clinical Sciences Lund, Lund University, Lund, Sweden
Corresponding author: Bo Ahrén, [email protected].
Received 12 January 2014 and accepted 10 March 2014.
developed on the basis that the gut-derived glucagon-like
peptide (GLP)-1 is a potent antidiabetic hormone due to
its ability to stimulate insulin secretion and inhibit glucagon secretion. DPP-4 inhibition prevents the inactivation
of GLP-1 and, therefore, raises the circulating intact (active) GLP-1 levels above physiological levels that have
antidiabetic actions.
After initial preclinical development, the first clinical
proof-of-concept study for DPP-4 inhibition was reported
in the early 2000s (2). DPP-4 inhibition was first approved for clinical use in 2006 with the DPP-4 inhibitor
sitagliptin, and thereafter, several other DPP-4 inhibitors
have been introduced into clinical practice (3). They are all
oral agents taken once or twice daily and are also being
developed for once-weekly administration. They reduce
fasting and postprandial hyperglycemia, have a low risk
for hypoglycemia, and are weight neutral (1). Currently,
they are mainly used as an add-on to metformin, but they
are also efficient in monotherapy in patients in whom
metformin is unsuitable and in combination with other
glucose-lowering agents.
THE CLASSICAL MECHANISM FOR THE
GLUCOSE-LOWERING EFFECT OF DPP-4
INHIBITION
DPP-4 is an enzyme that is widely expressed throughout
the body and abundantly expressed in endothelial cells.
It is attached to the intravascular portion of vascular
endothelial cells and also exists in a soluble circulating
form (4). It is a serine protease that cleaves peptides
between the amino acid 2 and 3 from the N-terminal
end, particularly if the second amino acid is alanine or
proline. GLP-1 has alanine as the second amino acid and
is therefore a substrate for DPP-4, which cleaves the intact GLP-17–36 to GLP-19–36, which is largely inactive. The
© 2014 by the American Diabetes Association. See http://creativecommons.org
/licenses/by-nc-nd/3.0/ for details.
diabetes.diabetesjournals.org
inactivation of GLP-1 by DPP-4 is rapid and extensive,
and it has been estimated that the increase in GLP-1
concentration in peripheral venous plasma amounts to
less than 10% of the increase in the portal concentration,
with the consequence that after DPP-4 inhibition, much
higher GLP-1 levels are seen in the portal vein than in
peripheral plasma, as has been demonstrated for vildagliptin in pigs (5).
The importance of removing the two N-terminal amino
acids in GLP-1 by DPP-4 for the rapid inactivation of GLP-1
in vivo was initially demonstrated by Holst and Deacon,
and they also showed that a DPP-4 inhibitor (valine
pyrrolidide) prevented the inactivation of exogenously
infused GLP-1, which augmented its insulinotropic effect
in pigs (6). All of the DPP-4 inhibitors used in clinical
practice have been shown to give robust and long-lasting
inhibition of plasma DPP-4 activity (7). Several of the
DPP-4 inhibitors have also been demonstrated to increase
levels of (intact) GLP-1 after meal ingestion (8–11). For
vildagliptin and sitagliptin, it has in addition been demonstrated that intact GLP-1 levels are increased not only
after meal ingestion, but also throughout the entire 24-h
period with elevated fasting levels (12,13).
Based on this knowledge, the classical mechanism for
DPP-4 inhibition is that due to prevention of inactivation
of GLP-1 in the peripheral circulation, the increased
circulating intact GLP-1 results in stimulated insulin
secretion and inhibited glucagon secretion, resulting in
increased glucose utilization and diminished hepatic glucose production, which, through reduction in postprandial
and fasting glucose, reduce HbA1c. However, several recent findings, mainly in acute studies in nondiabetic
rodents, have found that the classical mechanism of
DPP-4 inhibition to reduce glucose by inhibiting the enzyme in peripheral plasma, thereby raising circulating levels of intact GLP-1, may not explain the full power of this
approach and that tissue DPP-4 and/or neural effects may
also contribute. This Perspectives in Diabetes summarizes
these nonclassical effects to illustrate the mechanistic complexity of this strategy to lower glucose in type 2 diabetes.
DPP-4 INHIBITION IN THE GUT
As a challenge to the classical mechanism as the sole effect
of DPP-4 inhibition to improve glycemia, recent studies
have shown that DPP-4 inhibition can reduce glucose
without also inhibiting plasma DPP-4 activity in the
peripheral circulation; hence a nonsystemic plasma component seems to contribute. This idea was initially
presented by Waget et al. in 2011 in acute studies in
nondiabetic mice (14). They demonstrated that administration of low oral doses of sitagliptin (40–120 mg) improved glucose tolerance and increased circulating insulin
without affecting DPP-4 activity in peripheral plasma. It
should be emphasized that even though DPP-4 activity
was not altered in peripheral plasma, the glucose-lowering
effect of sitagliptin was still GLP-1 dependent since the
effect was lost in mice with genetic deletion of GLP-1
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2197
receptors (14). While not inhibiting DPP-4 activity in peripheral plasma, these low doses of sitagliptin inhibited
DPP-4 activity locally in the duodenum, jejunum, and
ileum. In the gut, DPP-4 is localized to capillaries that
are situated in close apposition to both the enteroendocrine cells and the nerve endings in the enteric autonomic
nervous system (15). Inhibition of gut DPP-4 activity thus
prevents the inactivation of intact GLP-1 immediately
after its release from the L cells, which raises the tissue
level of the active form of the hormone. This in turn may
activate the autonomic nerves as well as result in increased portal GLP-1 levels to augment the activation of
portal GLP-1 receptors. Therefore, the conclusion from
the study by Waget et al. is that sitagliptin at low doses
inhibits DPP-4 in the intestine compartment, which prevents the inactivation of GLP-1 immediately after its release from the L cells, rather than having an effect on
inactivation of GLP-1 in the peripheral circulation by
inhibiting DPP-4 activity in peripheral plasma.
We recently confirmed that DPP-4 inhibition can
reduce glycemia and increase insulin secretion by a mechanism independent of inhibition of DPP-4 activity in
peripheral plasma. The results are shown in Fig. 1. In
nondiabetic mice, the DPP-4 inhibitor vildagliptin was
administered at four different doses, and plasma DPP-4
activity was measured. We found a dose-response relationship between dose of vildagliptin and plasma DPP-4
activity. When, at the same time, an oral glucose tolerance
test with measurement of insulin secretion (insulinogenic
index) was undertaken, we also found that vildagliptin
dose-dependently improved insulin secretion and reduced
glycemia. However, by comparing the glucose and insulin
results with the inhibition of plasma DPP-4 activity, it is
seen that the two lowest doses of vildagliptin did not
significantly affect plasma DPP-4 activity yet clearly improved glycemia and increased insulin secretion. These
results therefore suggest that DPP-4 inhibition may occur
in the gut at lower dose levels of the DPP-4 inhibitors
than inhibit DPP-4 activity in peripheral plasma and that
this reduced gut DPP-4 activity prevents the inactivation
of gut GLP-1, which would raise tissue level and portal
level of intact GLP-1. This would be glucose lowering
through two mechanisms: by activating enteric afferent
autonomic nerves and by inhibiting hepatic glucose release through hepatoportal GLP-1 receptors.
Effects Through Neural Activation
The prevention of GLP-1 inactivation in the gut would
allow a more powerful stimulation of GLP-1 on the local
afferent gut autonomic nerves, which may in turn
stimulate insulin secretion and inhibit glucagon secretion
through a neural circuit since autonomic nerves are
involved in the regulation of islet hormone secretion
(16). The first suggestion that GLP-1 may stimulate insulin
secretin through activation of the autonomic nervous system was presented in 2000 by Balkan and Li who demonstrated that the blockade of autonomic ganglia prevents
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Glucose-Lowering DPP-4 Inhibitor Mechanisms
intraportally administered GLP-1 from stimulating insulin secretion in rats (17). Furthermore, we demonstrated
in 2004 that a low dose of GLP-1 given intravenously did
not stimulate insulin secretion in mice that had been
rendered insensitive to sensory nerve activation by the
neurotoxin capsaicin (18). These findings suggested that
GLP-1 had the capacity to activate afferent autonomic
nerves, in the gut and portal system, which, through central coupling mechanisms, activates efferent nerves that
stimulate insulin secretion. In 2007, Vahl et al. demonstrated that the GLP-1 receptor is expressed in the nodose
ganglia and in nerve terminals innervating the portal vein,
which provided a further support for a neural component
of GLP-1 effects (19). Vahl et al. also demonstrated that
portal infusion of a low dose of a GLP-1 receptor antagonist (des-His[1],Glu[9] exendin-4) resulted in glucose intolerance in rats, suggesting a neural effect. Insulin secretion
was the same after GLP-1 receptor antagonism as in controls, in spite of increased glucose levels, suggesting an
impaired insulin secretion. Since DPP-4 inhibition prevents the local inactivation of GLP-1 in the gut, the afferent component of the neural effect may be targeted by
the treatment. There is also a central component of the
autonomic mechanisms, because the activation of afferent
autonomic nerves results in central effects, which activates efferent nerves. It has also been reported that brain
GLP-1 is involved in the central neural effects since central activation of GLP-1 receptors stimulate insulin secretion (20). DPP-4 inhibitors probably do not, however,
target this central effect since DPP-4 is not expressed
centrally. The efferent neural component of the neural
circuit activated by gut/portal GLP-1 is most likely the
vagus nerve, which is an important regulator of islet function (16). This conclusion is also supported by findings that
portal GLP-1 administration stimulates the electrical activity in hepatic vagal afferents and pancreatic vagal efferents
Diabetes Volume 63, July 2014
in rats (21). A recent study also presented direct evidence
for a neural component of the glucose-lowering action of
DPP-4 inhibition (22). Thus Fujiwara et al. found that the
increase in insulin and reduction in glycemia achieved by
portal infusion of a DPP-4 inhibitor (diprotin A) were significantly reduced by hepatic vagotomy in Sprague-Dawley
rats.
Therefore it may be concluded that the prevention of
local inactivation of GLP-1 in the gut by DPP-4 inhibitors
may allow GLP-1 to activate these gut/portal afferent
nerves. A neural effect may also be of importance for the
effect of DPP-4 inhibition to inhibit glucagon secretion
since glucagon secretion is dependent on neural effects
(16), although this has not yet been studied and therefore
remains to be established.
Effects Through Insulin-Independent Mechanisms of
GLP-1
A major determinant of the reduction of fasting glucose
by DPP-4 inhibition is a reduction in hepatic glucose
output (11,12). This effect is mainly caused by reduction
of circulating glucagon through the GLP-1–induced inhibition of glucagon secretion since prevention of changes
in glucagon secretion also prevents GLP-1 from inhibiting
hepatic glucose output in humans (23). However, recent
studies suggest that there are indeed islet-independent
glycemic effects of GLP-1 mediated by the hepatic portal
system. Infusion of GLP-1 was found to reduce hepatic
glucose production independent of changes in insulin or
glucagon levels in dogs (24) and recently in humans (25).
The local prevention of GLP-1 inactivation by DPP-4 inhibition in the gut and hepatic portal system may increase
portal GLP-1 levels, allowing for such a direct effect of
GLP-1 to suppress hepatic glucose output through activating portal GLP-1 receptors, which is also evident from
several experimental studies (26,27). Indeed, there is
Figure 1—DPP-4 activity in peripheral plasma at 120 min after oral administration of the DPP-4 inhibitor vildagliptin at different doses or
placebo (left panel), the area under the 120 min glucose curve after oral administration of glucose (35 mg) with or without vildagliptin at
different doses (middle panel), and the 15 min insulinogenic index (15 min insulin level divided by the glucose level) after oral administration
of glucose (35 mg) with or without vildagliptin at different doses (right panel). All experiments were performed in anesthetized C57BL/6J
mice (n = 12 in each group), and samples were taken from the retro-orbital plexus in heparinized tubes and analyzed for DPP-4 (enzymatic
measure), glucose (glucose oxidase method), and insulin (radioimmunoassay). Asterisks indicate the probability level of random difference
when compared with placebo. *P < 0.05; **P < 0.01. AUC, area under the curve.
diabetes.diabetesjournals.org
a higher increase in circulating levels of intact GLP-1 in
the portal vein than in the peripheral circulation (5). We
also recently confirmed that DPP-4 inhibition can lower
glucose independent of changes in islet hormones in
humans since in a study of acute administration of sitagliptin to healthy subjects, postprandial plasma glucose
was significantly reduced without any differences in insulin or glucagon between the sitagliptin and placebo
groups (28). Together these findings suggest that DPP-4
inhibition may increase portal GLP-1 levels, which reduces
hepatic glucose output and increases peripheral glucose
utilization by islet hormone–independent mechanisms.
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vildagliptin prevented fat-induced pancreatic inflammation and peri-insulitis (36). This may be mediated by
the two incretin hormones since it has been shown that
treatment of splenic T cells with both GLP-1 and glucosedependent insulinotropic polypeptide (GIP) diminishes
pancreatic infiltration of T cells after splenic T cells are
injected into NOD mice (37). Hence, in addition to stimulating insulin secretion and inhibiting glucagon secretion
through preventing GLP-1 inactivation in islets, DPP-4
inhibition may also prevent islet inflammation as a mechanism for improving islet function.
DPP-4 INHIBITION IN PANCREATIC ISLETS
PREVENTION OF INACTIVATION OF OTHER
BIOLOGICALLY ACTIVE PEPTIDES THAN GLP-1
There is accumulating evidence that GLP-1 is expressed in
islets, which is not surprising considering its coding in the
proglucagon sequence in a-cells. It has, however, been
thought that proglucagon is processed to glucagon in
a-cells due to cell-specific expression of the processing
enzymes prohormone convertase 2. However, as recently
demonstrated by Marchetti et al. in human islets, GLP-1
may also be expressed in a-cells (29). It has also been
shown that under certain conditions, such as high glucose, GLP-1 production is increased in a-cells due to a specific overexpression of prohormone convertase 1/3 (30).
Therefore, in subjects with diabetes, there is the possibility that GLP-1 is produced in islets to such a degree that it
will be of relevance after DPP-4 inhibition. This assumption has become even more likely due to accumulating
evidence that DPP-4 is also expressed in islets. This was
initially demonstrated 20 years ago in studies in pig islets
where it was found to be localized to secretory granules of
the a-cells (31). We have also demonstrated that DPP-4 is
expressed in mouse and human islets and is exclusively
expressed in the a-cells in human islets (32). In line with
these observations, Shah et al. showed recently that longterm incubation of isolated human islets with high glucose, palmitate, and cytokines increases apoptosis and
impairs insulin secretion and that the DPP-4 inhibitor
linagliptin prevents this by stabilizing and increasing
GLP-1 secretion along with inhibited islet DPP-4 activity
(33). We have also confirmed stimulation of insulin secretion in isolated mouse islets using the DPP-4 inhibitor
NVP DPP728 (32). These findings therefore suggest that
a local islet mechanism may contribute to the increased
insulin secretion during DPP-4 inhibition.
A local islet effect may also have anti-inflammatory
effects, which may be of importance since local islet
inflammation may contribute to the development of
b-cell deterioration in type 2 diabetes. This may be caused
by cytokines released from infiltrating immune cells. An
additional mechanism may be that hyperglycemia may
cause a secretion of interleukin-1b from b-cells (34). A
recent study by Dobrian et al. reported that sitagliptin
reduces expression of inflammatory cytokines in islets
from dietary-induced obesity in mice (35). We also found
recently that chronic treatment of high-fat–fed mice with
DPP-4 inhibition may exert pleiotropic effects through
biologically active peptides that are substrates for DPP-4.
Indeed, several biological peptides apart from the GLP-1
are potentially substrates for DPP-4 although most of
these findings are not relevant in vivo (4). Indirect evidence that other peptides than GLP-1 may contribute to
the effects of DPP-4 inhibition was recently presented by
Aulinger et al. (38). They showed that the GLP-1 receptor
antagonist exendin-9 could inhibit the effect of sitagliptin
on glucose and insulin secretion by only ;50% after 4
weeks of treatment with the DPP-4 inhibitor in type 2
diabetes. An obvious candidate for the GLP-1 independent mechanism is the incretin hormone GIP since GIP
is inactivated by DPP-4 and stimulates insulin secretion,
although this effect is reduced in type 2 diabetes. This
would also be supported by animal studies showing that
the glucose-lowering action of DPP-4 inhibition is only
partially inhibited in mice with genetic deletion of
GLP-1 receptors (or GIP receptors) but totally suppressed
in mice with genetic deletion of both GIP and GLP-1
receptors (39). GIP may also be of relevance for the low
risk of hypoglycemia during treatment with DPP-4 inhibition since the peptide stimulates glucagon secretion
during hypoglycemia (40), which is an important counterregulatory mechanism allowing a preserved or even augmented glucagon secretion during hypoglycemia in
patients treated with DPP-4 inhibition, as has been demonstrated for vildagliptin (41).
There is also, however, potential for involvement of
nonincretin bioactive peptides in the effect of DPP-4
inhibitors. One such potential peptide is stromal-derived
factor (SDF)-1a. It is a small peptide chemokine that is
a substrate for DPP-4 since its active form (SDF-1a [1–68])
is rapidly degraded to an inactive form (SDF-1a [3–68]) by
the enzyme (42). A recent study showed that SDF-1a is
also expressed in rat islets, that its expression is increased
by cellular injury, and that SDF-1a increases the expression of prohormone convertase 1/3 in a-cells, which
increases the islet production of GLP-1 (43). In cellular
injury in islets, such as oxidative stress or glucolipotoxicity,
it is therefore possible that SDF-1a expression is increased with increased production of GLP-1 as a consequence. This would potentially be of relevance during
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Glucose-Lowering DPP-4 Inhibitor Mechanisms
DPP-4 inhibition when inactivation of both SDF-1a and
GLP-1 are inhibited, thereby facilitating further the intraislet GLP-1 production, with effects on insulin and glucagon secretion.
Another potential mediator of the insulinotropic effect of
DPP-4 inhibition is pituitary adenylate cyclase-activating
polypeptide (PACAP). It is a widespread neuropeptide that is
secreted by intraislet nerves and stimulates insulin secretion
(44). It is a substrate for DPP-4 (45), and therefore its rapid
inactivation might be inhibited during treatment with DPP4 inhibition. We have found a functional correlate to this in
that the insulinotropic action of intravenously injected
PACAP in mice is augmented by DPP-4 inhibition (46) and
that glucose tolerance after oral glucose administration is
impaired in mice with genetic deletion of PAC1 receptors
compared with wild-type mice (unpublished observations).
The potential contribution of prevention of PACAP inactivation by DPP-4 inhibition for the glucose-lowering action of
treatment remains to be studied in more detail since PACAP,
besides stimulating insulin secretion, also stimulates, and
does not inhibit, glucagon secretion (43). Nevertheless,
long-term administration of PACAP in animal models of
diabetes has been shown to improve glycemia (47).
CONCLUSIONS
This Perspectives in Diabetes has outlined pleiotropic
mechanisms that may contribute to the insulinotropic,
glucagonostatic, and glucose-lowering effect seen during
treatment with DPP-4 inhibitors. These effects, which
Diabetes Volume 63, July 2014
have been demonstrated in several experimental conditions in rodents and to a limited degree also in humans,
are illustrated together with the classical mechanism in
Fig. 2. The main conclusion is that changes in DPP-4
activity in peripheral plasma may not fully explain the
glucose-lowering ability of DPP-4 inhibition but that
effects on tissue DPP-4 activity may contribute, either
through effects of tissue-bound DPP-4 or DPP-4 in tissue
plasma. These pleiotropic actions of DPP-4 inhibition may
explain that DPP-4 inhibition reduces glucose almost as
much as GLP-1 receptor agonists, which have a stronger
direct GLP-1 receptor activation (48). The pleiotropic
effects will also allow differentiation in mechanisms
from other glucose-lowering strategies, including GLP-1
receptor agonists, and may also suggest that differentiation between the different DPP-4 inhibitions may not
entirely depend on different degrees of inhibition of
DPP-4 activity in peripheral plasma but may also be dependent on tissue penetration and local effects of DPP-4.
In fact, even nonabsorbed DPP-4 inhibitors may have
glucose-lowering actions through the inhibition of DPP-4
activity in the gut.
It should be emphasized that the evidence presented
here is based mainly on acute studies in nondiabetic
rodents. Therefore it is important to also explore the
potential of the nonclassical effects of DPP-4 inhibitors in
other models, including in subjects with type 2 diabetes.
A few studies already exist in humans, however, that
support the notion of a nonclassical mechanism for DPP-4
Figure 2—The classical and nonclassical mechanisms for the glucose-lowering effect of DPP-4 inhibition. GLP-17–36 is released from the
gut into the circulation and is rapidly degraded to the largely inactive GLP-19–36 by DPP-4. In the classical mechanism, DPP-4 inhibitors
inhibit DPP-4 in peripheral plasma, which prevents the inactivation of circulating intact GLP-1, which raises the circulating concentration of
intact GLP-17–36. This stimulates insulin secretion and inhibits glucagon secretion, which reduces hepatic glucose production and
increases fat and muscle glucose utilization, which lowers fasting and postprandial glucose. The nonclassical mechanisms of DPP-4
inhibition involve inhibition of gut DPP-4 activity, which raises tissue level of intact GLP-1 in the gut immediately after its release, in turn
activating gut autonomic nerves in addition to raising the portal concentration of intact GLP-1, thereby activating portal GLP-1 receptors.
Another nonclassical mechanism of DPP-4 inhibitors is inhibition of islet DPP-4, which prevents inactivation of islet GLP-1, thereby
improving islet function. Finally, DPP-4 inhibitors may also prevent the inactivation of other biologically active peptides than GLP-1,
such as GIP, SDF-1a, and PACAP, which may result in improved islet function.
diabetes.diabetesjournals.org
inhibition. Thus it has been demonstrated in subjects with
type 2 diabetes both for sitagliptin (14) and vildagliptin
(49) that insulin secretion also after intravenous glucose
administration is stimulated during DPP-4 inhibition with
no or only minimal increase in circulating GLP-1 levels,
which would suggest contribution by autonomic nerves
and/or other bioactive peptides. A finding by Salehi
et al. that GLP-1 receptor antagonism reduces the insulin
response to intravenous glucose in humans may support
the neural hypothesis (50). Furthermore, studies in
healthy subjects (28) and in subjects with type 2 diabetes
(11) have shown that sitagliptin can reduce glucose without increasing circulating insulin, which also suggests
nonclassical mechanisms. Further studies are, however,
important, and these should also include exploration of
the relative impact of these different mechanisms. Studies
in subjects with autonomic neuropathy also need to be
undertaken to explore whether diabetes neuropathy
would affect the neural signaling involved in the glucoselowering action of DPP-4 inhibition. It should also be emphasized that even though effects of DPP-4 inhibitors that
are different from changes in DPP-4 activity in peripheral
plasma seem to contribute to their glucose-lowering action,
it is not possible to distinguish whether the effect is mediated through local cell-associated or tissue DPP-4 or
whether it is actually plasma DPP-4 activity present in
virtually all tissue compartments. Future studies have to
develop novel techniques to distinguish between these different tissue components of DPP-4 to establish the mechanisms and plasma versus nonplasma site of action of DPP-4
inhibitors. The conclusion that can be firmly drawn now is
that changes in peripheral plasma DPP-4 activity to prevent the inactivation of circulating GLP-1 cannot fully
account for the mechanism of DPP-4 inhibitors to lower
glucose and, therefore, that nonclassical pleiotropic mechanisms may exist for the glucose-lowering action of DPP-4
inhibition.
Acknowledgments. The authors are grateful to Kristina Andersson for
technical assistance in the work by the authors.
Funding. This work was supported by grants from the Swedish Research
Council, Region Skåne, and the Lund University Faculty of Medicine.
Duality of Interest. B.A. has received honoraria for participation in advisory
boards and/or speaking fees or research grants from AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Merck, Novartis, Novo Nordisk, Sanofi, and Takeda,
all of which are companies producing DPP-4 inhibitors or GLP-1 receptor agonists.
No other potential conflicts of interest relevant to this article were reported.
Author Contributions. The manuscript was written by B.O. and B.A. B.A.
is the guarantor of this work and, as such, had full access to all the data in the
study and takes responsibility for the integrity of the data and the accuracy of the
data analysis.
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